The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo.
1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
Ichinose
M
M
Department of Thoracic Medicine, National Heart & Lung Institute, London.
Barnes
P J
PJ
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*
D006020:Glycopeptides; D011480:Protease Inhibitors; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; D002216:Captopril; D011433:Propranolol; D015097:3-Mercaptopropionic Acid; D001121:Lysine Carboxypeptidase; D001920:Bradykinin; C008890:phosphoramidon